Personalized medicine

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A presentation on personalized medicine to a 4th year biotechnology class at Carleton University.

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  • Excess amounts can lead to bone marrow toxicity, reducing the normal amounts of white and red blood cells
  • 6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism. This alters the synthesis and function of RNA and DNA.
  • congestive heart failure—the progressive weakening of the heart muscle to the point where it can no longer pump blood efficiently
  • Most drug-metabolizing enzymes exhibit clinically relevant genetic polymorphisms.
    Essentially all of the major human enzymes responsible for modification of functional groups [classified as phase I reactions (left)] or conjugation with endogenous substituents [classified as phase II reactions (right)] exhibit common polymorphisms at the genomic level;
    Those enzyme polymorphisms that have already been associated with changes in drug effects are separated from the corresponding pie charts.
    The percentage of phase I and phase II metabolism of drugs that each enzyme contributes is estimated by the relative size of each section of the corresponding chart. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH:quinone oxidoreductase or DT diaphorase; COMT, catechol O-methyltransferase; GST, glutathione S-transferase; HMT, histamine methyltransferase; NAT, N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5'-triphosphate glucuronosyltransferases.
  • Figure 4. Pharmacogenetics of Nortriptyline. Mean plasma concentrations of nortriptyline after a single 25-mg oral dose are shown in subjects with 0, 1, 2, 3, or 13 functional CYP2D6 genes.
    In addition, some subjects with ultrarapid metabolism have been shown to have multiple copies of the CYP2D6 gene. 18 Such
    subjects can have an inadequate therapeutic response to standard doses of the drugs metabolized by CYP2D6. Although the occurrence of multiple
    copies of the CYP2D6 gene is relatively infrequent among northern Europeans, in East African populations, the allele frequency can be as high as 29
    percent. 22 The effect of the number of copies of the CYP2D6 gene — ranging from 0 to 13 — on the pharmacokinetics of the antidepressant drug nortriptyline is shown in Figure 4. 23 There could hardly be a more striking illustration of how genetics influences the metabolism of a drug.
  • Approximately 5 to 10 percent of white subjects were found to have a relative deficiency in their ability to oxidize the antihypertensive drug debrisoquin. They also had an impaired ability to metabolize the antiarrhythmic and oxytocic drug sparteine. Subjects with poor metabolism of these
    two drugs had lower urinary concentrations of metabolites and higher plasma concentrations of the parent drug than did subjects with extensive metabolism
    A plot of the ratio of urinary debrisoquin to 4-hydroxydebrisoquin — a so-called metabolic ratio — is shown in Figure 3. The higher the metabolic ratio, the less metabolite was excreted. Therefore, subjects with poor metabolism are shown, counterintuitively, at the far right of the graph, with a few subjects at the far left of the frequency distribution who are now classified as having ultrarapid metabolism. As described subsequently, suchsubjects may have multiple copies of the gene for CYP2D6. Therefore, debrisoquin and sparteine represented “probe drugs” — compounds that could be used to classify subjects as having either poor metabolism or extensive metabolism. That strategy, the administration of a probe compound metabolized by a genetically polymorphic enzyme, became a standard technique used in many pharmacogenetic studies.
  • Drugミdrug interactions. The molecular basis of a drug-drug interaction. The orphan nuclear receptor PXR is a transcription factor that regulates the expression of the CYP3A gene (yellow) in the liver and intestine. It functions as a heterodimer with the nuclear receptor RXR. Drug A binds to PXR and induces expression of the CYP3A enzyme (pink), accelerating the metabolism of drug B, which is a substrate for CYP3A. CYP, cytochrome P450; OH, hydroxyl group; PXR, pregnane X receptor; RXR, retinoid X receptor.
  • Figure 1. The Incidence-Rate Ratio for Sudden Death from Cardiac Causes According to the Current Use of the Study Antibiotic Medications and CYP3A Inhibitors.
    The bars indicate 95 percent confidence intervals. The reference group for the incidence-rate ratio associated with the concurrent use of erythromycin and CYP3A inhibitors and with the use of CYP3A inhibitors alone is the patients who used none of these medications; that for the incidence-rate ratio associated with the use of erythromycin and use of amoxicillin, regardless of the use of CYP3A inhibitors, is the patients who used neither of these antibiotic medications.
  • Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.
    Figure 1. Metabolic Pathways of Codeine Biotransformation.
    The conversion of codeine into norcodeine by CYP3A4 and into codeine-6-glucuronide by glucuronidation usually represents 80 percent of codeine clearance, and conversion of codeine into morphine by CYP2D6 represents only 10 percent of codeine clearance (blue arrows). Morphine is further metabolized into morphine-6-glucuronide and into morphine-3-glucuronide. Morphine and morphine-6-glucuronide have opioid activity (green arrows). Glucuronides are eliminated by the kidney and are thus susceptible to accumulation in cases of acute renal failure. The patient (red arrows) had ultrarapid CYP2D6 metabolism, inhibition of CYP3A4 as a result of treatment with clarithromycin and voriconazole, and glucuronide accumulation due to acute renal failure. Red arrows with dotted lines indicate low levels of drug conversion or elimination, green arrows with dotted lines indicate low levels of brain penetration, and thick arrows indicate high levels.
  • Personalized medicine

    1. 1. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine Michel Dumontier, Ph.D. Associate Professor of Bioinformatics Department of Biology, Institute of Biochemistry, School of Computer Science Carleton University Ottawa Institute for Systems Biology Ottawa-Carleton Institute for Biomedical Engineering Nov 18, 2010
    2. 2. Dumontier::BIOL4301:Personalized Medicine “If it were not for the great variability among individuals, medicine might as well be a science and not an art” Sir William Osler, 1892
    3. 3. Dumontier::BIOL4301:Personalized Medicine SNPs – a major source of variation • Single Nucleotide Polymorphisms (SNPs) – Single base change in DNA AAGCCTA AAGCTTA – SNPs arise as a consequence of mistakes during normal DNA replication – Average frequency 1/1000bp • Other sources of variation – Insertions, deletions, translocation, duplications, repeats – copy number variation is a major element SNP Deletion Translocation Insertion Most Common
    4. 4. Dumontier::BIOL4301:Personalized Medicine Human Variation • In human beings, 99.9 percent bases are same. • Remaining 0.1 percent (~3M bases) makes a person unique. – Different attributes / characteristics / traits • how a person looks, • diseases he or she develops. • These variations can be: – Harmless (change in phenotype) – Harmful (diabetes, cancer, heart disease, Huntington's disease, and hemophilia ) – Latent (variations found in coding and regulatory regions, are not harmful on their own, and the change in each gene only becomes apparent under certain conditions e.g. susceptibility to lung cancer)
    5. 5. Dumontier::BIOL4301:Personalized Medicine
    6. 6. Dumontier::BIOL4301:Personalized Medicine
    7. 7. Dumontier::BIOL4301:Personalized Medicine
    8. 8. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine The ability to offer • The Right Drug • To The Right Patient • For The Right Disease • At The Right Time • With The Right Dosage Genetic and metabolic data will allow drugs to be tailored to patient subgroups
    9. 9. Dumontier::BIOL4301:Personalized Medicine Benefits of Personalized Medicine • Better matching patients to drugs instead of “trial and error • Customized pharmaceuticals may eliminate life- threatening adverse reactions • Reduce costs of clinical trials by – Quickly identifying total failures – Favourable responses for particular backgrounds • Improved efficacy of drugs
    10. 10. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine : BiDil • Combination pill containing two medications for heart failure, cardiovascular disease, and/or diabetes. • Clinical trials did not show overall benefit across entire population. • Subgroup of patients showed best overall benefit – BiDil approved solely for use in African-descent patients. Controversial!
    11. 11. Dumontier::BIOL4301:Personalized Medicine PGx • Pharmacokinetics – What the body does to the drug – dose, dosage regimen, delivery form – Drug fate: Absorption, distribution, metabolism, and elimination of drugs (ADME) • Pharmacodynamics – What the drug does to the body – Biochemical and physiological effects of drugs – mechanism of drug action – relationship between drug concentration and effect • Pharmacokinetics and pharmacodynamics are essential to assess the drug efficacy.
    12. 12. Dumontier::BIOL4301:Personalized Medicine
    13. 13. Dumontier::BIOL4301:Personalized Medicine PGx + genetics/genomics • Pharmacogenetics – The effect of genetic variation on drug response. • Pharmacogenomics – The application of genomics to the study of human variability in drug response. • Pharmacogenetics and pharmacogenomics are expected to play an important role in the development of better medicines for populations and targeted therapies with improved benefit/risk ratios for individuals
    14. 14. Dumontier::BIOL4301:Personalized Medicine Cytochrome P450 Enzymes In bacteria, fungi, insects, plants, fish, mammals Catalyze monooxygenation reaction: RH + 2H+ +O2 + NADPH  ROH + H2O + NADP+ Act on: – Endogenous substrates (cholesterol, steroids, fatty acids) – Exogenous (drugs, food additives, environmental toxins) Involved in – Production of steroids – Metabolism of fatty acids, prostaglandins, leukotrienes, retinoids – Activation or inactivation of therapeutic agents – Enzyme activation/inhibition resulting in drug-drug interactions, adverse events
    15. 15. Dumontier::BIOL4301:Personalized Medicine Drug-Metabolizing Enzymes Pharmacogenomics: Translating Functional Genomics into Rational Most DME have clinically relevant polymorphisms Those with changes in drug effects are separated from pie. Phase I: modification of functional groups Phase II: conjugation with endogenous substitutents
    16. 16. Dumontier::BIOL4301:Personalized Medicine CYP enzymes are involved in the metabolism of clinically important drugs CYP Enzyme Examples of substrates 1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 17β-Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19); 2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane 2D6 Acetaminophen, Codeine, Debrisoquine 3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R- Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine S. Rendic Drug Metab Rev 34: 83-448, 2002
    17. 17. Dumontier::BIOL4301:Personalized Medicine S. Rendic Drug Metab Rev 34: 83-448, 2002 Red indicates enzymes important in drug metabolism Factors Influencing Activity and Level of CYP Enzymes Nutrition 1A1;1A2; 1B1, 2A6, 2B6, 2C8,9,19; 2D6, 3A4,5 Smoking 1A1;1A2, 2E1 Alcohol 2E1 Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5 Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5 Genetic Polymorphism 2A6; 2C9,19; 2D6;
    18. 18. Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537 Nortriptyline (anti-depressant) Pharmacogenetics
    19. 19. Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537 Use of probe drugs to determine metabolic activity due to CYP2D6 variants Antihypertensive debrisoquin decreases blood pressure
    20. 20. Dumontier::BIOL4301:Personalized Medicine CYP3A4 • Abundant in liver and intestines and accounts for nearly 50% of CYP450 enzymes. • Activity can vary markedly among members of a population – Constitutive variability is ~5-fold but can increase to 400-fold through induction and inhibition • Activity affected by other drugs: – Grapefruit juice is an inhibitor Felodipine is a calcium channel blocker (calcium antagonist), a drug used to control hypertension (high blood pressure) 5mg tablet with juice
    21. 21. Dumontier::BIOL4301:Personalized Medicine
    22. 22. Dumontier::BIOL4301:Personalized Medicine Quantitative Structure-Activity Relationship (QSAR) • find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds. • extract features (hydrophobicity, pK, van der Waals radii, hydrogen bonding energy, conformation) • build mathematical relationship f(activity|features) • automatically assesses the contribution of each feature • can be used to make predictions on a new molecule
    23. 23. Dumontier::BIOL4301:Personalized Medicine 3D QSAR for CYP3A4
    24. 24. Dumontier::BIOL4301:Personalized Medicine 3D QSAR for CYP3A4 with known substrates
    25. 25. Dumontier::BIOL4301:Personalized Medicine
    26. 26. Dumontier::BIOL4301:Personalized Medicine Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002 CYP3A4 mediated Drug-Drug Interaction PXR: pregnane X receptor; RXR: retinoid X receptor • Protect against xenobiotics • Diverse drugs activate through heterodimer complex • Cause drug-drug interactions
    27. 27. Dumontier::BIOL4301:Personalized Medicine
    28. 28. Dumontier::BIOL4301:Personalized Medicine Codeine Metabolism Gasche Y et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. NEJM 2004 • 80% codeine normally converted to glucuronide, eliminated by kidney. • 5-10% codeine is metabolized into morphine by CYP2D6 • inhibition of CYP3A4 or rapid metabolic variants of CYP2D6 during renal failure would show toxicity – 7% of caucasians have a nonfunctional CYP2D6 variant – <2% are CYP2D6 ultrarapid metabolizers which may suffer from opioid intoxication
    29. 29. Dumontier::BIOL4301:Personalized Medicine Diagnostics AmpliChip CYP450: Range of drug metabolism phenotypes is observed for individuals based upon the cytochrome P-450 genes
    30. 30. Dumontier::BIOL4301:Personalized Medicine
    31. 31. Dumontier::BIOL4301:Personalized Medicine Known side effects Unavoidable Avoidable Medication errors Product quality defects Preventable adverse events Injury or death Remaining uncertainties • Unexpected side effects • Unstudied uses • Unstudied populations Sources of risk from drug products FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation
    32. 32. Dumontier::BIOL4301:Personalized Medicine LIPITOR: Known Side Effects • Lipitor blocks the production of cholesterol in the body. • May reduce risk of hardening of the arteries, which can lead to heart attacks, stroke, and peripheral vascular disease
    33. 33. Dumontier::BIOL4301:Personalized Medicine FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation Drug recalls are surprisingly common Drug Recalls 191 226 248 352 354 254 215 401 60 53 34 88 72 156 83 88 71 101 248 316 176 72 0 300 600 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Fiscal year Number Prescription Over-the-counter
    34. 34. Dumontier::BIOL4301:Personalized Medicine Many reasons for drug recalls Reported Drug Quality Defects Other, 9% Contamination/ sterility, 3% Fill problem, 4% Packaging, 6% Delivery system, 10% Product defect, 14% Formulation/ substitution, 22% Adverse drug reports, 18% Labeling, 14% Fiscal year 2005 FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation
    35. 35. Dumontier::BIOL4301:Personalized Medicine Treatment for Acute Pain increased risk of heart attack and stroke (after 18 months) VIOXX: Unknown Side Effects
    36. 36. Dumontier::BIOL4301:Personalized Medicine Vioxx targets prostaglandin biosynthesis • Prostaglandins, derivatives of C20 fatty acids, often trigger pain, fever, and inflammation. • Aspirin, Ibuprofen, acetominaphen are non-steroidal anti-inflammatory drugs (NSAIDS) that inhibit prostaglandin H2 synthase (A.K.A. COX) – no pain.
    37. 37. Dumontier::BIOL4301:Personalized Medicine • 3 isoforms: COX-1, COX-2, COX-3. • COX-1 constitutively expressed • COX-2 only expressed in response to inflammation • Drugs were designed to fit into COX-2 active site channel, but not COX-1 (20% smaller channel) • Vioxx & Celebrex lack non-specific side effects of NSAIDS, but Vioxx caused cardiac side effects & was withdrawn in 2004
    38. 38. Dumontier::BIOL4301:Personalized Medicine in silico Drug Discovery • Need 3D structure • Scan a virtual library of small molecules and “dock” them to a site of interest on a protein structure • Predict binding energy • Filters thousands of compounds relatively quickly • Top hits can be used for more rigorous computational/experimental characterization and optimization
    39. 39. Dumontier::BIOL4301:Personalized Medicine Successful drug discovery strategies involve computational and experimental approaches oral bioavailabity binding Less pain Fewer side effects repeat…
    40. 40. Dumontier::BIOL4301:Personalized Medicine synthesis of compound ↓ manipulation of structure to get better drug (greater efficacy, fewer side effects)Aspirin
    41. 41. Dumontier::BIOL4301:Personalized Medicine
    42. 42. Dumontier::BIOL4301:Personalized Medicine "When you're studying human genetics, you're studying the information that goes into the making of man and how that information flows from one generation to the next. To be able to do that well, you have to know the population structure. We can basically take the list that includes everyone in the country or 2,000 people with schizophrenia. We can know within minutes exactly how everyone is related to everyone else, which is key for being able to study the genetics of anything in a sensible manner." deCODE Genetics in Reykjavik, Iceland. Country-wide genotyping and family tree reconstruction
    43. 43. Dumontier::BIOL4301:Personalized Medicine deCODE Genetics For example, deCODE has used the Icelandic family tree to look at people who are taking statins. Approximately 10,000 people in Iceland take statins, but about 2,000 of those don't respond. The list of patients who don't respond can be run through the genealogy database. "I can tell you that they are related to each other, and we can get families that have a structure that allows us to map a gene that indicates a lack of response to statins."
    44. 44. Dumontier::BIOL4301:Personalized Medicine
    45. 45. Dumontier::BIOL4301:Personalized Medicine Things to Consider • Does my doctor know enough about genomic medicine to be advising me? – Are there genetic counselors available? • Will the test only be for this condition? – What if I am susceptible to another disease? • Who will know about this? – Doctors… insurance companies? • How exactly will the results be kept secure and in confidence?
    46. 46. Dumontier::BIOL4301:Personalized Medicine How much will this cost? • More drugs may succeed in clinical trials due to positive outcome for smaller subset – Will pharma attempt to recoup costs with a pricier drug? • Will public health cover the costs of genetic testing? – Reduce overall health cost due to fewer ADRs – Should we determine clinically validated genes or should we sequence the genome? • How will insurance premiums be affected?
    47. 47. Dumontier::BIOL4301:Personalized Medicine There is still lots to figure out… • Science still early. Limited data in public domain. • Many variations not clinically significant • Expensive to test for genotype (currently) • Ethical issues in testing individual genotype • Unclear how to deliver information to the practitioner
    48. 48. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine: What’s your take?
    49. 49. Dumontier::BIOL4301:Personalized Medicine dumontierlab.com michel_dumontier@carleton.ca

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